Pharmacokinetics and biological activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin

Abstract

Concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rat liver and adipose tissue, and hepatic ethoxyresorufin O-deethylase (EROD) activity were studied subsequent to a single subcutaneous injection of TCDD. Two types of experiments were performed to study: (a) time-dependent changes following a single injection of 300 ng TCDD/kg body wt (points 1-4), and (b) dose-dependent changes measurable after 7 days following a single injection (points 5-7). 1. Absorption of TCDD following a single subcutaneous injection was about 90% after 3 days and 98% after 5 days. 2. Following a single dose of 300 ng TCDD/kg body wt peak concentrations were: liver (after 3 days): 4.7 +/- 0.9 ng/g wet wt, and adipose tissue (after 7 days): 0.82 +/- 0.07 ng/g wet wt. 3. T1/2 of TCDD in liver was 13.6 days over the total experimental period (from day 10 to 91 of the study), apparently with an initial faster phase: 11.5 days (from day 10 to 49), and a slower period at the end of the experiment: 16.9 days (from day 49 to 91); in adipose tissue the t1/2 was 24.5 days (from day 14 to 91 of the study). 4. Maximum induction of EROD in the liver was observed (14-fold at 300 ng TCDD/kg body wt) 3-7 days following the injection; the activity was decreased to about one third of the maximum 3 weeks after the injection; increase in total cytochrome P-450 at this dose was only about 1.4-fold at the induction maximum. 5. The ratio of the TCDD concentrations in liver and adipose tissue increased considerably between doses of 3 ng TCDD/kg body wt (ratio: about 0.74) and 3000 ng TCDD/kg body wt (ratio: about 7.7). 6. The extent of EROD induction in the liver increased dose dependently. A significant effect was first observed with a dose of 3 ng TCDD/kg body wt (activity about +32% above control activity). The corresponding tissue concentration was about 10 pg TCDD/g liver wet wt. 7. An almost perfect linear relationship exists (when using a double-log plot) between the hepatic TCDD concentration and the EROD activity for tissue concentrations ranging from 40 to 30,000 pg TCDD/g wet wt.

Accelerator mass spectrometry in biomedical dosimetry: relationship between low-level exposure and covalent binding of heterocyclic amine carcinogens to DNA.

“…To evaluate this possibility and to ensure that our procedures adequately purify DNA, we measured DNA adduct formation with TCDD, a carcinogen that has not been found to covalently bind to DNA (19,20 and -33% of the administered dose should reach the liver tissue within the time frame of this study (21). These distribution kinetics are similar to that expected for MeIQx (22).…”

CYP1A2 is not required for 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced immunosuppression

“…These results indicate that hepatomegaly, and assumed liver sequestration of TCDD, in CYP1A2 (−/−) knockout mice is inhibited compared to that in CYP1A2 (+/+) wild-type and CYP1A2 (+/−) heterozygous mice. While TCDD is highly lipophilic, and partitions into more lipid-rich tissues on a physical basis (Jackson et al, 1993), its distribution in tissue, particularly the liver, is dose-dependent (Diliberto et al, 1995(Diliberto et al, , 2001Kedderis et al, 1993;Abraham et al, 1988). Sequestration of TCDD, and TCDD-like congeners, in the liver of mice has been linked to a strong affinity association with CYP1A2 (Voorman and Aust, 1989;Poland et al, 1989).…”

Long-term carcinogenesis studies on 2,3,7,8-tetrachlorodibenzo-p-dioxin and hexachlorodibenzo-p-dioxins

“…At low doses, percentage adsorption varies with the dosing vehicle, and may increase as the dose level decreases (Abraham et al, 1988). Absorption may be reduced if the TCDD is adsorbed onto solids such as food or soil.…”

“…However, most rodent studies were conducted at relatively high doses, capable of inducing binding proteins. Abraham et al (1988Abraham et al ( , 1989a demonstrated that with decreasing dose, the ratio of fiver to fat concentrations decreased. At low doses corresponding to environmental levels, ratios in rodents and primates are not expected to differ.…”

“…The half-life in rats was 31 days and 11 days in mice and hamsters. However, at high doses in laboratory studies enzyme induction occurs, and the metabolic elimination of TCDD correspondingly increases (Abraham et al 1988). At low doses half-life as a proportion of life span may be similar across species.…”